More than 20 million people each year undergo surgery in the U.S.A. Post-operative cognitive dysfunction (POCD), a documented clinical entity that occurs more frequently in elderly patients, has drawn significant attention from the public and professionals. Because the issue is obviously significant, there is an urgent need to identify interventions to attenuate POCD. Our preliminary study showed that amantadine, a clinically used anti-viral agent that is also used in treating various neurodegenerative diseases, reduced surgery (right carotid exploration)-induced learning and memory impairment as well as neuroinflammation in young adult rats. Amantadine also increased glial cell-derived growth factor (GDNF) in the brain. GDNF has been shown to reduce microglial activation in a previous study. In addition, our preliminary study showed that amantadine attenuated surgery-induced learning and memory impairment in elderly rats. We hypothesize that GDNF mediates the amantadine effects on surgery-induced neuroinflammation as well as learning and memory impairment in aged rats. In this project, we will determine whether: 1) the duration of amantadine application affects the effectiveness of amantadine to attenuate surgery-induced learning and memory impairment in aged rats; 2) amantadine reduces surgery-induced neuroinflammation through GDNF; and 3) inhibition of GDNF blocks amantadine-induced attenuation of cognitive impairment after carotid arterial exploration. We will use old adult male rats and subject them to right carotid arterial exploration. Animals will be anesthetized by the volatile anesthetic isoflurane. Learning and memory will be evaluated by Barnes maze and fear conditioning. Various brain regions will be harvested for biochemical examination. These studies may provide preclinical evidence for using amantadine to attenuate POCD. Our studies may also reveal target molecules for the amantadine effects, which may help design interventions for POCD.